Prenatal diagnosis of CLOVES syndrome confirmed by detection of a mosaic PIK3CA mutation in cultured amniocytes

Abstract

Congenital lipomatous asymmetric overgrowth of the trunk, lymphatic, capillary, venous, and combined-type vascular malformations, epidermal nevi, skeletal and spinal anomalies (CLOVES) syndrome, a segmental overgrowth syndrome, is caused by post zygotic somatic mutations in PIK3CA, a gene involved in the receptor tyrosine kinase phosphatidylinositol 3-kinase (PI3)-AKT growth-signaling pathway. Prenatal ultrasound findings of lymphovascular malformations, segmental overgrowth and skeletal defects can raise suspicion for CLOVES syndrome, but molecular confirmation of PIK3CA mutations on prenatally obtained samples is challenging because of somatic mosaicism. We detected a mosaic disease-causing mutation in PIK3CA by sequencing of DNA extracted from cultured amniotic cells, but not from DNA directly prepared from an amniotic fluid sample in a fetus with prenatally suspected CLOVES syndrome. The infant was born prematurely and displayed severe lymphovascular malformations and segmental overgrowth consistent with a clinical diagnosis of CLOVES syndrome; he passed away at 29 days of life. We discuss the complexities and limitations of genetic testing for somatic mosaic mutations in the prenatal period and highlight the potential need for multiple approaches to arrive at a molecular diagnosis. © 2014 Wiley Periodicals, Inc.

Keywords: lipomatous malformation; mosaicism; prenatal diagnosis; somatic overgrowth; vascular anomalies.

Fig. 1

Prenatal images at 27 weeks gestation and postnatal images of the infant after birth at 31 weeks. A: T2-weighted coronal MR image of the fetus at 27 weeks. There is extensive infiltration by the malformations through the subcutaneous tissues of the abdominal wall, from the axillae to the pelvis, including the dorsal upper thigh on the left. Macrocystic structures are noted (arrows), and there is large-volume ascites. B: Maximum Intensity Projection (MIP) T2-weighted MR image of the limb overgrowth affecting the left foot, with wide-spaced macrodactyly. Multiple sequences showed enlargement of the entire left lower extremity compared with the right, though without abnormal high signal that would indicate infiltration by a mass in the lower leg. C: One day-old infant with bilateral asymmetric overgrowth of the chest and abdomen, bilateral linear epidermal nevi. D: Asymmetric overgrowth of left lower limb, showing macrodactyly, furrowed foot sole and a sandal gap between first and second toes.

Fig. 2

The PIK3CA c.1624G>A (p.E542K) mutation detected in this patient using Next Generation Sequencing. The data are visualized in the Integrative Genomics Viewer (IGV)(top) and confirmed by Sanger sequencing (bottom).